Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox–Gastaut syndrome, ESES: A functional framework

Berg, Anne T.; Gaebler‐Spira, Deborah; Wilkening, Greta N.; Zelko, Frank; Knupp, Kelly G.; Dixon‐Salazar, Tracy; Villas, Nicole; Meskis, Mary Anne; Harwell, Vinez; Thompson, T.; Sims, Scotty; Nesbitt, Gerry

doi:10.1016/j.yebeh.2020.107287

Cited by 31 publications

(39 citation statements)

References 30 publications

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“…In collaboration with parents representing different DEE family groups, including the KCNQ2 Cure Alliance and the Jack Pribaz Foundation, a survey was developed to assess not only seizures but also several areas of functional and developmental impairment and other concerns identified by parents. Details of the survey development were presented previously 8 . Where possible, we utilized existing instruments or modified them and incorporated parent feedback in determining response options.…”

Section: Methodsmentioning

confidence: 99%

“…Details of the survey development were presented previously. 8 Where possible, we utilized existing instruments or modified them and incorporated parent feedback in determining response options. The survey was designed as a series of topic-specific forms for seizures, gross and fine motor abilities, communication, feeding, behavior, sleep, gastrointestinal function, vision, hearing, and other outcomes.…”

Section: Methodsmentioning

confidence: 99%

“…A full report on functional abilities in KCNQ2 and other DEE groups has been published previously. 8 Parents were asked about the frequency of sleep disturbances due to seizures and independent of seizures. For these analyses, we focused on nonseizure-related nocturnal awakenings as reported in the past month (6-7 nights/week, 1-5 nights/week, and <1/week, including none).…”

Section: Methodsmentioning

confidence: 99%

“…A sum of the four domains in which there was significant impairment, dependence, or delay was constructed. A full report on functional abilities in KCNQ2 and other DEE groups has been published previously 8 …”

Section: Methodsmentioning

confidence: 99%

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KCNQ2‐DEE: developmental or epileptic encephalopathy?

Berg

Mahida

Poduri

2021

Ann Clin Transl Neurol

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Objective KCNQ2‐associated developmental and epileptic encephalopathies (DEE) present with seizures and developmental impairments. The relation between seizures and functional impairments in affected children and the relation of a specific genetic variant to seizure control remains unknown. Methods Parents of children with documented KCNQ2 variants who participated in a structured, online natural history survey provided information about seizure history, functional mobility, hand use, communication function, and feeding independence. Bivariate analyses were performed with nonparametric methods and logistic regression was used for multivariable analyses. Results Thirty‐nine children (20, 51% girls, median age 4.5 years, interquartile range (IQR) 1.9—19.3) had a median age of seizure onset of 1 day (IQR 1—3 days). The most common seizure types were bilateral tonic‐clonic (N = 72, 28%) and bilateral tonic (N = 13, 33%). Time since last seizure was <6 months (N = 18, 46%), 6–23 months (N = 11, 28%), and ≥24 months (N = 10 26%). Severe functional impairment was reported for mobility (62%), hand grasp (31%), feeding (59%), and communication (77%). Twenty‐eight (72%) were impaired in ≥2 domains. There were only weak and inconsistent associations between seizure recency and individual impairments or number of impairments after adjustment for other factors. The functional location of the variants within the Kv7.2 protein was not associated with seizure control. Interpretation Seizures in KCNQ2‐DEE are often well‐controlled, but children have severe impairments regardless. With the increased potential for precision therapies targeting the Kv7.2 channel or the KCNQ2 gene itself, identifying the most relevant and sensitive clinical endpoints will be critical to ensure successful trials of new therapies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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KCNQ2‐DEE: developmental or epileptic encephalopathy?

Berg

Mahida

Poduri

2021

Ann Clin Transl Neurol

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“…Based on an initial survey of parents conducted by the PACS1 Syndrome Research Foundation, areas of greatest concern for patients with PACS1 -disorder were identified. We then adapted and augmented a series of parent-reported interview forms already utilized in over 200 families of children with developmental epilepsies and encephalopathies (DEE) [ 9 ]. Content included a medical checklist, seizure history, functional abilities, early academic skills, self-care, and therapies.…”

Section: Methodsmentioning

confidence: 99%

PACS1-Neurodevelopmental disorder: clinical features and trial readiness

Nuland

Reddy

Quassem

et al. 2021

Orphanet J Rare Dis

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Background PACS1-Neurodevelopmental Disorder (PACS1-NDD) is an ultra-rare condition due to a recurrent mutation in the PACS1 gene. Little systematically collected data exist about the functional abilities and neurodevelopmental morbidities in children with PACS1-NDD Methods Parents of individuals with PACS1-NDD completed an on-line survey designed collaboratively by researchers, parents, and clinicians. Analyses focused on those with a confirmed R203W variant. Results Of 35 individuals with confirmed variants, 18 (51%) were female. The median age was 8 years (interquartile range 4.5–15). Seventeen (49%) had a diagnosis of epilepsy. Twelve (40%, of 30 responding to the question) reported autism and (N = 11/30, 37%) reported features of autism. Most children walked independently (N = 29/32, 91%), had a pincer grasp (N = 23/32, 72%), could feed themselves independently (N = 15/32, 47%), and used speech (N = 23/32, 72%). Sixteen of twenty-nine (55%) had simple pre-academic skills. Neither epilepsy nor autism was associated with functional abilities or other clinical features (all P > 0.05). Conclusions PACS1-NDD is a moderately-severe intellectual disability syndrome in which seizures occur but are not a defining or primary feature. Successful precision medicine clinical trials for this ultra-rare disorder must target important core features of this disorder and utilize assessment tools commensurate with the level of function in this clinical population.

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Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities

Knowles,

Warren,

Mohamed

et al. 2024

Ann Clin Transl Neurol

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Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease‐modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving “drops,” but should incorporate additional patient‐centered outcomes, using emerging measures adapted to people with LGS. Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient‐centered clinical trials that are tailored to LGS pathophysiology and natural history.

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Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox–Gastaut syndrome, ESES: A functional framework

Cited by 31 publications

References 30 publications

KCNQ2‐DEE: developmental or epileptic encephalopathy?

KCNQ2‐DEE: developmental or epileptic encephalopathy?

PACS1-Neurodevelopmental disorder: clinical features and trial readiness

Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities

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